Discovery of novel small-molecule Src kinase inhibitors via a kinase-focused druglikeness rule and structure-based virtual screening
Discovery of novel small-molecule Src kinase inhibitors via a kinase-focused druglikeness rule and structure-based virtual screening
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通过以激酶为中心的药物相似性规则和基于结构的虚拟筛选发现新型小分子 Src 激酶抑制剂
DOI：
10.1080/08927022.2013.809717
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发表时间：
2014-01
影响因子：
2.1
通讯作者：
Wei Fu
中科院分区：
文献类型：
--
作者：
Lili Xu;Qing Shen;Xianfeng Gu;Wei Fu
非受体酪氨酸激酶Src的过表达与多种人类癌症的发生和进展有关。阻断Src介导的信号通路被认为是一种有前途的抗癌策略。我们在此报告的发现新的小分子Src抑制剂的晶体结构为基础的虚拟筛选。提出了一种以激酶为中心的类药规则，并将其应用于化合物库的设计。用DOCK进行大规模对接和用GOLD进行再评分的组合导致6个命中，其具有针对Src的中等至有效的抑制活性。其中，化合物1的IC50为1.2 μM，显示出最强的抑制活性。通过使用分子对接，构建了前3个命中（按效力和配体效率排名）与Src的结合模型，以提供同时利用铰链区中的氢键相互作用和后口袋中的疏水堆积的合理策略。该方法对Src抑制剂的进一步结构化药物设计具有指导意义。
Overexpression of the non-receptor tyrosine kinase Src is implicated in the development and progression of various human cancers. Blocking signalling pathways mediated by Src is believed to be a promising anticancer strategy. We report herein the discovery of novel small-molecule Src inhibitors by crystal structure-based virtual screening. A kinase-focused druglikeness rule was proposed and used in the design of compound library. Combination of large-scale docking with DOCK and rescoring with GOLD resulted in 6 hits with moderate to potent inhibitory activity against Src. Among them, compound 1 with an IC50 of 1.2 μM shows the most potent inhibitory activity. By using molecular docking, binding models of the top 3 hits (ranked by potency and ligand efficiency) with Src were constructed to provide a rational strategy that simultaneously exploits hydrogen bonding interaction in the hinge region and hydrophobic stacking in the back pocket. This approach is instructive and meaningful to further structure-based drug design of Src inhibitors.
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影响因子：
3.1
作者：
Gucalp A;Sparano JA;Caravelli J;Santamauro J;Patil S;Abbruzzi A;Pellegrino C;Bromberg J;Dang C;Theodoulou M;Massague J;Norton L;Hudis C;Traina TA
通讯作者：
Traina TA
影响因子：
7.3
作者：
Miteva, MA;Lee, WH;Villoutreix, BO
通讯作者：
Villoutreix, BO
影响因子：
--
作者：
J. Biscardi;D. Tice;S. Parsons
通讯作者：
J. Biscardi;D. Tice;S. Parsons
影响因子：
50.5
作者：
Campone, M.;Bondarenko, I.;Epstein, R. J.
通讯作者：
Epstein, R. J.
影响因子：
3.5
作者：
Hirayama, Kazunori;Aoki, Shunsuke;Wada, Keiji
通讯作者：
Wada, Keiji